The Akt/mTOR and MNK/eIF4E Pathways Rewire the Prostate Cancer Translatome to Secrete HGF, SPP1 and BGN and Recruit Suppressive Myeloid Cells - Beyond the Abstract
Prostate cancer cells hijacking the translation machinery to sustain immune evasion means that these cancer cells have found a way to manipulate the cellular process of protein synthesis for their benefit. The translation machinery refers to the complex cellular components and processes responsible for translating genetic information (mRNA) into functional proteins.
By altering the production of specific proteins, the cancer cells can manipulate the immune environment around the tumor and create favorable conditions for their continued growth and evasion of immune surveillance.
The study identified three key ligand-receptor pairs Bgn-Tlr2, Spp1-Cd44, and Hgf-Met, that are the most highly expressed, translationally regulated, among the identified ligand-receptor pairs derived from the extracellular interactome between prostate cancer and MDSCs (Myeloid-Derived Suppressor Cells). Bgn, Spp1, and Hgf mediate the recruitment and potentiate the suppressive function of MDSCs, which inhibit T cell proliferation and activity and promote tumor growth.
The silencing of Bgn, Spp1, and Hgf in prostate cancer mouse models decreased MDSC recruitment and reduced tumor growth.
These three MDSC recruiters were highly expressed in advanced human prostate cancer and correlated with the CD33 myeloid marker, indicating their relevance in prostate cancer progression.
The study found increased eIF4e phosphorylation and downregulation of the tumor suppressor PDCD4 in both mouse and human prostate cancer. These alterations led to efficient translation of Bgn, Spp1, and Hgf compared to normal prostate.
The researchers tested two translation inhibitors, eFT508, and ipatasertib, in two prostate cancer models to block eIF4e phosphorylation and rescue PDCD4 levels, respectively. The dual treatment with these inhibitors reduces MDSCs recruitment and tumor growth. Moreover, the treatment with eFT508 or ipatasertib enhances the efficacy of immunotherapy based on CXCR2 antagonist.
These findings suggest that targeting the translation machinery, specifically by blocking eIF4e phosphorylation and rescuing PDCD4 levels, may represent a potential therapeutic vulnerability of prostate cancer cells.
Understanding how prostate cancer cells exploit the translation machinery to sustain immune evasion is crucial for developing targeted therapies. By identifying and targeting the specific proteins or processes involved in this hijacking, researchers can potentially disrupt the immune evasion mechanism and enhance the immune response against prostate cancer cells.
It is important to note that this research is still at the experimental stage, and further studies, including clinical trials, will be needed to fully validate the findings and assess the feasibility and safety of targeting the translation machinery as a treatment strategy for prostate cancer. Continued research in this field holds promise for developing new strategies to overcome immune evasion in prostate cancer and improve treatment outcomes.
The discovery made by the Institute of Oncology Research (IOR) researchers provides valuable insights into the mechanisms of immune evasion in prostate cancer and opens up new possibilities for developing more effective treatment options.
Written by: Daniela Brina, PhD, Institute of Oncology Research, Milan, Italy
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Translational Regulation in Prostate Cancer: The Akt/mTOR and MNK/eIF4E Pathways Unveiled - Daniela Brina